This invention relates to novel cyclic substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 mediated diseases.
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1a, IL-1b or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROxcex1, GROxcex2, GROxcex3and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAa, b and g respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the a-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8Rb, which has high affinity for IL-8 as well as for GROxcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 a or b receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or (II).
The present invention also provides for the novel compounds of Formula (I), and (II) and pharmaceutical compositions comprising a compound of Formula (I), and (II) and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein
R is xe2x80x94NHxe2x80x94C(X1)xe2x80x94NHxe2x80x94(CR13R14)vxe2x80x94Z;
X1 is oxygen or sulfur;
Z is W, HET, 
xe2x80x83an optionally substituted C1-10 alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
X is Nxe2x80x94R18, O, C(O) or C(R19)2;
R1 is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, (CR8R8)qS(O)tR4, hydroxy, hydroxy C1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, heteroaryl C1-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, C(O)R11, (CR8R8)qC(O)OR12, (CR8R8)qOC(O) R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2R17, or (CR8R8)qS(O)2NR4R5; or two R1 moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
p is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
s is an integer having a value of 1 to 3;
t is 0, or an integer having a value of 1 or 2;
v is 0, or an integer having a value of 1 to 4;
HET is an optionally substituted heteroaryl;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
R6 is independently hydrogen, halogen, C1-10 alkoxy, optionally substituted C1-4 alkyl, halosubstituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4 alkyl;
Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, (CR8R8)qS(O)tR4, hydroxy, hydroxyC1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, arylC1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8; (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)qC(O)OR12, (CR8R8)qOC(O) R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)q NHS(O)2Ra, or (CR8R8)qS(O)2NR4R5; or two Y moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 and R14 are independently hydrogen, optionally substituted C1-4 alkyl, or one of R13 and R14 may be optionally substituted aryl;
R15 and R16 are independently hydrogen or an optionally substituted C1-4 alkyl,
R17 is C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 4alkyl;
R18 is hydrogen, optionally substituted C1-10 alkyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
R19 is independently hydrogen, halogen, C1-10 alkyl, NR4R5, C1-10 alkyl-NR4R5, C(O)NR4R5, optionally substituted C1-10 alkyl, halosubstituted C1-10 alkyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, or heteroaryl C1-4 alkyloxy;
Ra is NR4R5, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
W is 
xe2x80x83the E containing ring is optionally selected from 
the asterix * denoting point of attachment of the ring;
or a pharmaceutically acceptable salt thereof.
Compounds of Formula (II) useful in the present invention are represented by the structure: 
wherein
R is xe2x80x94NHxe2x80x94C(X1)xe2x80x94NHxe2x80x94(CR13R14)vxe2x80x94Z;
X1 is oxygen or sulfur;
Z is W, HET, 
xe2x80x83an optionally substituted C1-10 alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
X is N, or CR6;
R1 is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, (CR8R8)qS(O)tR4, hydroxy, hydroxy C1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, heteroaryl C1-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, C(O)R11, (CR8R8)qC(O)OR12, (CR8R8)qOC(O) R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2R17, or (CR8R8)qS(O)2NR4R5; or two R1 moieties together may form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
p is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
s is an integer having a value of 1 to 3;
t is 0, or an integer having a value of 1 or 2;
v is 0, or an integer having a value of 1 to 4;
HET is an optionally substituted heteroaryl;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
R6 is hydrogen, halogen, C1-10 alkoxy, optionally substituted C1-4 alkyl, halosubstituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4 alkyl;
Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, (CR8R8)qS(O)tR4, hydroxy, hydroxyC1-4alkyl, aryl, aryl C1-4 alkyl, aryloxy, arylC1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)qC(O)OR12, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2Ra, or (CR8R8)qS(O)2NR4R5; or two Y moieties together may form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
R13 and R14 are independently hydrogen, optionally substituted C1-4 alkyl, or one of R13 and R14 may be optionally substituted aryl;
R17 is C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4alkyl;
R18 is hydrogen, optionally substituted C1-10 alkyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
R19 is independently hydrogen, halogen, C1-10 alkyl, NR4R5, C1-10 alkyl NR4R5, C(O)NR4R5, optionally substituted C1-10 alkyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, or heteroaryl C1-4 alkyloxy;
Ra is NR4R5, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
W is 
xe2x80x83the E containing ring is optionally selected from 
the asterix * denoting point of attachment of the ring;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula (I) and (II) may also be used in association with the veterinary treatment of mammals, other than. humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 xcex1 and xcex2 receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
As readily seen, the difference between compounds of Formula (I) and (II) lies in the unsaturation of the hetero containing ring, and hence the substitutions on the X and the double bond. The remaining terms, defined below, are the same for both compounds of Formula (I) and (II) unless otherwise indicated.
Suitably R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl, such as CF3; C1-10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; C1-10 alkoxy, such as methoxy, or ethoxy; halosubstituted C1-10 alkoxy, such as trifluoromethoxy; azide; (CR8R8)qS(O)tR4, wherein t is 0, 1 or 2; hydroxy; hydroxy C1-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C1-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C1-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)qC(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)qC(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; (CR8R8)qC(O)OR12; (CR8R8)qOC(O)RI 1; (CR8R8)qNR4C(O)R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)qNR4C(NR5)R11; (CR8R8)qNHS(O)2R17; (CR8R8)qS(O)2NR4R5; or two R1 moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring. All of the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below.
For use herein the term xe2x80x9cthe aryl, heteroaryl, and heterocyclic containing moietiesxe2x80x9d refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term xe2x80x9cmoietiesxe2x80x9d and xe2x80x9cringsxe2x80x9d may be interchangeably used throughout.
It is recognized that R1 moiety may be substituted on either the benzene ring or the X containing ring, if possible.
When R1 forms a dioxybridge, s is preferably 1. When R1 forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other R1 moieties as defined above.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
Suitably, R8 is independently hydrogen or C1-4 alkyl.
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, R10 is C1-10 alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
Suitably, R11 is hydrogen, C1-4 alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl.
Suitably, R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.
Suitably, R13 and R14 are independently hydrogen, or an optionally substituted C1-4 alkyl which may be straight or branched as defined herein, or one of R13 and R14 are an optionally substituted aryl.
Suitably, v is 0, or an integer having a value of 1 to 4.
When R13 or R14 are an optionally substituted alkyl, the alkyl moiety may be substituted one to three times independently by halogen; halosubstituted C1-4 alkyl such as trifluoromethyl; hydroxy; hydroxy C1-4alkyl; C1-4 alkoxy; such as methoxy, or ethoxy; halosubstituted C1-10 alkoxy; S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4R5; or C(O)OR8.
Suitably, R17 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
Suitably, Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; (CR8R8)qS(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic C1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)qC(O)NR4R5; (CR8R8)qC(O)NR4R10; S(O)3H; S(O)3R8; (CR8R8)qC(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; (CR8R8)qC(O)OR12; (CR8R8)qOC(O) R11; (CR8R8)qC(NR4)NR4R5; (CR8R8)qNR4C(NR5)R11; (CR8R8)qNR4C(O)R11; (CR8R8)qNHS(O)2Ra; or (CR8R8)qS(O)2NR4R5; or two Y moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
When Y forms a dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. These ring systems may be substituted 1 to 3 times by other Y moieties as defined above.
Suitably, Ra is NR4R5, alkyl, aryl C1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
Y is preferably a halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio C1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2xe2x80x2- position or 2xe2x80x2-, 3xe2x80x2-position.
While Y may be substituted in any of the ring positions, n is preferably one. While both R1 and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
In compounds of Formula (I), R is xe2x80x94NHxe2x80x94C(X1)xe2x80x94NHxe2x80x94(CR13R14)vxe2x80x94Z.
Suitably, Z is W, HET, 
an optionally substituted C1-10 alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl.
Suitably, p is an integer having a value of 1 to 3.
X1 is oxygen or sulfur, preferably oxygen.
Suitably when Z is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system. If the HET moiety is a multi ring system, the ring containing the heteroatom does not need to be directly attached to the urea moiety through the (R13R14)v linkage. Any of the ring(s) in these systems may be optionally substituted as defined herein. Preferably the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring. Other rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
The HET ring may be optionally substituted independently one to five, preferably 1 to 3 times by Y as defined above. The substitutions may be in any of the ring(s) of the HET system, such as in a benzimidazole ring.
Suitably R15 and R16 are independently hydrogen, or an optionally substituted C1-4 alkyl as defined above for R13 and R14.
Suitably, W is 
Suitably, the E containing ring is optionally selected from 
the asterix * denoting point of attachment of the ring.
The E ring denoted by its point of attachment through the asterix (*) may optionally be present. If it is not present the ring is a phenyl moiety which is substituted by the R1 terms as shown. The E ring may be substituted by the (Y)n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
While Y in the W term may be substituted in any of the 5 ring positions of the phenyl moiety (when E is absent), Y is preferably mono-substituted in the 2xe2x80x2- position or 3xe2x80x2- position, with the 4xe2x80x2- preferably being unsubstituted. If the phenyl ring is disubstituted, substituents are preferably in the 2xe2x80x2or 3xe2x80x2 position of a monocyclic ring. While both R1 and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
Suitably, for compounds of Formula (I), X is Nxe2x80x94R18, O, C(O) or C(R19)2.
Suitably, R18 is hydrogen, optionally substituted C1-10 alkyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted. Preferably, for compounds of formula (I), R18 is hydrogen or alkyl, more preferably hydrogen.
Suitably, R19 is independently hydrogen, halogen, C1-10 alkyl, NR4R5, C1-10 alkyl-NR4R5, C(O)NR4R5, optionally substituted C1-10 alkyl, halosubstituted C1-10 alkyl C1-10 alkoxy, halosubstituted C1-10 alkoxy, hydroxy, aryl, aryl C1-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, or heteroaryl C1-4 alkyloxy;
For compounds of Formula (II) X is N, or CR6.
Suitably, R6 is hydrogen, halogen, C1-10 alkoxy, optionally substituted C1-4 alkyl, halosubstituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or an optionally substituted heterocyclic C1-4 alkyl.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C1-10alkyl; C1-10 alkoxy, such as methoxy or ethoxy; S(O)mxe2x80x2C1-10 alkyl, wherein mxe2x80x2 is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR4R5 group; NHC(O)R4; C(O)NR4R5; C(O)OH; S(O)2NR4R5; NHS(O)2R20, C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted C1-10 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C1-10 alkoxy; S(O)mxe2x80x2C1-10 alkyl; amino, mono and di-substituted amino, such as in the NR4R5 group; C1-10 alkyl, or halosubstituted C1-10 alkyl, such as CF3.
R20 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclicalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
The term xe2x80x9carylalkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
The term xe2x80x9cwherein two R1 moieties (or two Y moieties) may together form a 5 or 6 membered saturated or unsaturated ringxe2x80x9d is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Exemplified compounds of Formula (I) include:
N-[8-(3,4-Dihydro-1H-2,1-benzothiazine, 2,2-dioxide)]-Nxe2x80x2-[2-bromophenyl]urea;
N-[8-(4-Keto-3,4-dihydrosulfostyril)]-Nxe2x80x2(2-bromophenyl)urea
Exemplified compounds of Formula (II) include:
N-[8-(Sulfostyril)]-Nxe2x80x2-[2-bromophenyl]urea
For purposes herein the ring systems for compounds of Formula (I) and (II) are named as follows for illustration only with v=0, and Z is phenyl:
For compounds of Formula (I): 
X=N, X1=O, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-1H-2,1,4-benzothiadiazin-8-yl)-Nxe2x80x2-phenylurea
X=N, X1=S, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-1H-2,1,4-benzothiadiazin-8-yl)-Nxe2x80x2-phenylthiourea
X=C, X1=O, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-1H-2,1-benzothiazin-8-yl)-Nxe2x80x2-phenylurea
X=C, X1=S, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-1H-2,1-benzothiazin-8-yl)-Nxe2x80x2-phenylthiourea
X=C(=O) i.e. carbonyl, X1=O, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-8-yl)-N xe2x80x2-phenylurea
X=C(=O) i.e. carbonyl, X1=S, v=0, and Z is an unsubstituted phenyl
N-(3,4-Dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-8-yl)-Nxe2x80x2-phenylthiourea
For compounds of Formula (II): 
wherein
X=N, X1=O, v=0, and Z is an unsubstituted phenyl
N-(2,2-Dioxido-1H-2,1,4-benzothiadiazin-8-yl)-Nxe2x80x2-phenylurea
X=N, X1=S, v=0, and Z is an unsubstituted phenyl
N-(2,2-Dioxido-1H-2,1,4-benzothiadiazin-8-yl)-Nxe2x80x2-phenylthiourea
X=C, X1=O, v=0, and Z is an unsubstituted phenyl
N-(2,2-Dioxido-1H-2,1-benzothiazin-8-yl)-Nxe2x80x2-phenylurea
X=C, X1=S, v=0, and Z is an unsubstituted phenyl
N-(2,2-Dioxido-1H-2,1-benzothiazin-8-yl)-Nxe2x80x2-phenylthiourea
The compounds of Formula (I) and (II) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the producing of Formula (I) having a variety of different R, R1, and Ar groups which are reacted, employing optional substituents which are suitably protected to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with compounds of Formula (I) this is merely for illustration purposes only. 
If the desired heterocyclic compound 6-scheme 1 is not commercially available, the commercially available sulfonic acid can be converted to the corresponding sulfonyl chloride using a chlorinating agent such as thionyl chloride. The thionyl chloride 2-scheme 1 can be reacted with a commercially available aniline. The ester can be hydrolyzed using basic conditions such as 10% NaOH. The acid 3-scheme 1 can be cyclized under acidic or lewis acidic conditions such as polyphosphoric acid or AlCl3. The ketone can be converted to the double bond through formation of the hydrazine followed by rearrangement to the double bond under basic conditions. If substitution is desired on the sulfonamide ring it can be produced by alkylation of the compound 4-scheme-1 using standard conditions such as reaction with an alkyl halide in the presence of a base. The acidic nitrogen on compound 4-scheme-1 may have to be temporarily protected with a suitable protecting group such as an allyl, sulfonamide or BOM group.(Green ref) Alternatively compound 6-scheme-1 can be functionalized using a Michael reaction involving a functionalized organo cuprate. A number of other reactions can also be used to functionalize the double bond such epoxidation followed by epoxide opening, bromination followed by alkylation, and Diels-Alder reactions. 
If the desired aniline 3-scheme 2 is not commercially available the corresponding nitro compound can be prepared from 1-scheme 2, under standard nitration conditions (using HNO3 or NaNO3) at 23xc2x0 C. The nitro compound can then be reduced to the corresponding aniline using SnCl2 in EtOH. (or alternately LiAlH4). 
If the desired aniline 2-scheme 3 is not commercially available the nitro compound can be prepared from 2-scheme 2, which can then be reduced to the corresponding aniline using H2/Pd in EtOH. 
Ortho substituted heterocyclic phenyl ureas in 2-scheme 4 may be prepared by standard conditions involving the condensation of the commercially available optionally substituted (aryl or alkyl) isocyanate or thioisocyanate (Aldrich Chemical Co., Milwaukee, Wis.) with the corresponding aniline 1-scheme 4 in an aprotic solvent such as (DMF, toluene). 
If the desired heterocyclic compound 3-scheme 5 is not commercially available then it can be prepared by condensing the commercially available sulfonyl chloride 2-scheme 1 with 2-nitro aniline followed by hydrolysis to the acid 2-scheme 5. The acid can be cyclized by treatment with SOCl2 then AlCl3 in CH2Cl2. The corresponding aniline and the ortho substituted phenyl urea may be prepared using conditions outlined in scheme 2 and scheme 4. 
If the desired heterocycle 3-Scheme 6 is not available it can be synthesized from the corresponding commercially available amino phenol and chloromethyl sulfonyl chloride under basic conditions(such as triethyl amine or potassium carbonate). The corresponding aniline and the ortho substituted phenyl urea may be prepared using conditions outlined in scheme 2 and scheme 4. If substitution is desired on the sulfonamide ring it can be produced by alkylation of the compound 3-scheme-6 using standard conditions such as reaction with an alkyl halide in the presence of a base. The acidic nitrogen on compound 3-scheme-6 may have to be protected with a suitable protecting group such as an allyl, sulfonamide or BOM group. 
If the desired heterocycle 3-Scheme 7 is not available in can be synthesized from the corresponding commercially available phenylenediamine and chloromethyl sulfonyl chloride under basic conditions(such as triethyl amine or potassium carbonate). The corresponding aniline and the ortho substituted phenyl urea may be prepared using conditions outlined in scheme 2 and scheme 4. If substitution is desired on the sulfonamide ring it can be produced by alkylation of the compound 3-scheme-7 using standard conditions such as reaction with an alkyl halide in the presence of a base. The acidic nitrogen on compound 3-scheme-7 may have to be protected with a suitable protecting group such as an allyl, sulfonamide or BOM group. In the case where R18 is H the compound 3-scheme-7 can be oxidized to the imine using MnO2.